Myostatin, also referred to as growth differentiation factor-8 (GDF-8), is a member of the TGF-β superfamily of proteins, which shares structural similarities with other TGF-β family members. Myostatin is expressed largely in developing and adult skeletal muscle and functions as a negative regulator of skeletal muscle. Myostatin may also be involved in other physiological processes including preadipocyte differentiation to adipocytes, and, indirectly, with glucose homeostasis and inhibition of bone formation.
Growth differentiation factor-11, also referred to as GDF-11 or BMP-11, is the member of the TGF-β superfamily of proteins that is most homologous to myostatin. The amino acid sequence of the mature forms of human myostatin and GDF-11 are about 90% identical; however, GDF-11 is expressed in a wider range of tissues than is myostatin, including dental pulp, brain, heart, kidney and lung as well as muscle and adipose tissue. Human GDF-11 has recently been found to govern the temporal windows during which multipotent progenitors retain competence to produce distinct neural progeny.
There is a therapeutic need to specifically inhibit a myostatin activity while minimally inhibiting an activity of other TGF-β superfamily proteins, particularly GDF-11. Furthermore, there is a diagnostic need for an anti-myostatin antibody that minimally cross-reacts with another TGF-β superfamily protein, particularly GDF-11, in order to more accurately monitor or determine myostatin levels in a sample. Anti-myostatin antibodies that preferentially bind myostatin over GDF-11 are disclosed in International Publication Number WO 2005/094446. Humanized monoclonal antibodies which preferentially bind myostatin over GDF-11 are disclosed in International Publication Number WO 2007/044411.
Therapeutic antibodies may be subject to a variety of degradation reactions, e.g., deamidation or cleavage, that may occur in vivo or during manufacturing, formulation, storage and therapeutic use. For example, Asparagine (Asn) residues in antibodies or other polypeptides are particularly susceptible to cleavage in aqueous solution. Thus, there is a need for an anti-myostatin antibody that preferentially binds myostatin over GDF-11, has a strong binding affinity for myostatin (i.e., no greater than about 3×10−8 M) and is resistant to chemical degradation.